We have revealed the existence of leptin and corticosterone-dependent, fasting-induced up-regulation of type 2 deiodinase (D2) in arcuate nucleus astrocytes and tanycytes, the main types of glial cells in the hypothalamus. In addition, a direct relationship was established between these D2-containing, and hence triiodothyronine (T3)-producing, glial elements and components of the melanocortin system, including the neuropeptide Y (NPY)/agouti-related protein (AgRP)-expressing arcuate nucleus neurons. We have shown that arcuate nucleus NPY cells express mitochondria! uncoupling protein 2 (UCP2), the expression level and activity of which are regulated by thyroid hormones, T3 in particular. Furthermore, our findings showed that activation of UCP2 can lead to elevated local temperature, mitochondrial number and ATP levels, all of which enhance neuronal activity. We propose that elevated corticosterone and diminished leptin levels during negative energy balance triggers T3-regulated neuronal mitochondria! uncoupling in NPY/AgRP neurons, a key mechanism that allows NPY neurons to learn and remember the depletion of energy stores. This process entails mitochondrial proliferation and increased available ATP levels in NPY/AgRP neurons. This, in turn, will enable elevated NPY/AgRP- and suppressed POMC neuronal activity despite of increasing metabolic signals in the circulation following re-feeding. These hypotheses will be tested in this proposal. SPECIFIC AIM 1: To demonstrate the cellular consequences of D2-regulated UCP2 activity in NPY/AgRP neurons. SPECIFIC AIM 2: To determine the role of corticosteroids in the induction of D2-dependent UCP2 activity in NPY/AgRP neurons in a fasting-re-feeding paradigm. SPECIFIC AIM 3: To show that failed interplay between hypothalamic D2 and UCP2 impairs appropriate behavioral and endocrine responses following chronic negative energy balance, such as occurs following fasting. Understanding hypothalamic inter- and sub-cellular mechanisms that underlie positive energy balance in the face of adequate available energy sources will lead to the development of better strategies to combat metabolic disorders, including obesity and diabetes.